Variation within the MAPT (microtubule-associated protein tau) and SNCA (alpha-synuclein) genes is associated with a wide range of neurodegenerative disorders. Point mutafions in MAPT result in frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and triplications of SNCA cause hereditary eariy-onset parkinsonism with dementia. These rare variants have well-studied and relatively large effects on gene function that include altering splice isoform ratios (tau) and increasing expression of wild-type protein (SNCA). Common haplotypes across MAPT are associated with suscepfibility for Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Parkinson's disease (PD). The identity of the funcfional MAPT risk variants in these disorders has yet to be determined but appears to be disfinct between the tauopathies (AD, PSP, and CBD) and PD. Similariy, common haplotypes and a dinucleotide repeat-polymorphism (REP1) in SNCA confer risk for PD through mechanisms that are not cleariy understood. Finally, the AP0E*4 allele is a well-established susceptibility factor for AD, and there is some evidence that it might increase risk for dementia in PD. Therefore, given that MAPT, SNCA, and APOE play a role in multiple disease traits characterized by parkinsonism and/or dementia, these three genes might well influence the occurrence of cognifive impairment (Cl) and the rate of progression of Cl in PD. We further hypothesize that genefic variation within MAPT and SNCA mediates the development of Cl and rate of cognitive decline in PD by altering expression or splicing isoform ratios of tau and alpha-synuclein. Project 3 will test these hypotheses by accomplishing the following specific aims: (1) Determine whether MAPT, SNCA, and APOE genotypes or haplotypes are associated with cognifive function in a cross secfional analysis of 600 pafients with PD; (2) Determine whether MAPT, SNCA, and APOE genotypes or haplotypes are associated with rate of cognitive decline in a longitudinal analysis of the same cohort of pafients with PD; (3) Examine the associafion of MAPT and SNCA genotypes or haplotypes with tau and alpha-synuclein (total levels, phosphorylated species, isoform rafios) in CSF from 100 cognifively intact controls. The recent discovery of genetic risk factors for PD has uncovered a wealth of information that has opened exciting new avenues of research. Similar work to discover genetic risk factors for Cl in PD is equally promising but has lagged behind, largely due to limited access to cognitively well-characterized patient populations. Successful completion of our Aims will address this issue and the knowledge gained has the potential to generate novel experimental models, discover promising targets for therapeutic intervenfion, and identify subgroups of pafients and at risk subiects appropriate for specific clinical trials. RELEVANCE (See instructions): Existing treatment options for cognitive impairment (Cl) in PD are of limited benefit and the development of improved therapeutic strategies is very much needed. The work proposed in the application has the potential to increase our understanding of the genetic processes that underiie Cl in PD. This knowledge might serve to identify novel therapeufic targets which could be used to prevent and better treat this disabling facet of PD.